Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens

J Immunol. 1999 Feb 15;162(4):1884-8.

Abstract

We generated transgenic mice for STAT-4, a regulatory protein specifically associated with IL-12 signaling, under the control of a CMV promoter. These mice expressed strikingly increased nuclear STAT-4 levels in lamina propria CD4+ T lymphocytes upon systemic administration of dinitrophenyl-keyhole limpet hemocyanin and developed chronic transmural colitis characterized by infiltrates of mainly CD4+ T lymphocytes. The latter cells produced predominantly TNF and IFN-gamma but not IL-4 upon activation with alphaCD3/CD28 or autologous bacterial Ags, consistent with a Th1-type cell response. Furthermore, chronic colitis in STAT-4 transgenic mice could be adoptively transferred to SCID mice by colonic and splenic CD4+ T cells that were activated with Ags from autologous bacterial flora. These data establish a critical molecular signaling pathway involving STAT-4 for the pathogenesis of chronic intestinal inflammation, and targeting of this pathway may be relevant for the treatment of colitis in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer* / methods
  • Animals
  • Antigens, Bacterial / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Chronic Disease
  • Colitis / genetics
  • Colitis / immunology*
  • Colitis / microbiology
  • Colitis / pathology*
  • Crosses, Genetic
  • Cytokines / biosynthesis
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Haptens / immunology
  • Hemocyanins / immunology
  • Interferon-gamma / biosynthesis*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred Strains
  • Mice, SCID
  • Mice, Transgenic
  • STAT4 Transcription Factor
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Trans-Activators / biosynthesis
  • Trans-Activators / genetics*
  • Tumor Necrosis Factor-alpha / biosynthesis*

Substances

  • 2,4-dinitrophenyl keyhole limpet hemocyanin
  • Antigens, Bacterial
  • Cytokines
  • DNA-Binding Proteins
  • Haptens
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Hemocyanins